Hydroxyethylene dipeptide isosteres ("peptide mimics" or "peptidomimetics," illustrated below) are compounds in which a peptide bond is replaced with a non-hydrolyzable hydroxyethyl isostere that mimics a peptide enzymic transition state. Compounds incorporating hdyroxyethyl isosteres have recently generated considerable interest due to their ability to act as HIV-protease and renin inhibitors. Szelke, M., Jones, D. M., Hallet, A., Leckie, B. J., Proc. Am. Pept. Symp. 8th, 1983, 579; Meek, T. D., J. Enz. Inhib., 1992, 6, 65. The amino alcohol functionality in active peptidomimetics has (4S,5S) stereochemistry, as indicated below. Peptidomimetics also possess a substituent at the C2 position with the indicated absolute configuration. The "S" or "R" designation of the C2-substituent is a function of substituent priority. ##STR1##
Large quantities of hydroxyethylene dipeptide HIV-protease inhibitors and renin inhibitors are currently in demand for laboratory and clinical testing as well as for potential commercialization. Many of the prior synthetic approaches to these isosteres employ the lactone 1 as a key intermediate which is derivatized via diastereoselective alkylation of the enolate followed by ring opening. Several groups have synthesized 1 from .alpha.-amino aldehydes in a variety of ways, including by: (a) addition of a homoenolate equivalent (DeCamp, A. E., Kawaguchi, A. T., Volante, R. P., Shinkai, I., Tetrahedron Lett., 1991, 32, 1867); (b) addition of lithium ethyl propiolate (Fray, A. H., Kaye, R. L., Kleinman, E. F., J. Org. Chem., 1986, 51, 4828); (c) addition of allylic organometallic reagents (Vara Prasad, J. N. V., Rich, D. H., Tetrahedron Left., 1990, 31, 1803); or (d) by conversion of .alpha.-amino aldehydes into .alpha.-amino epoxides (Evans, B. E., Rittle, K. E., Homnick, C. F., Springer, J. P., Hirshfield, J., Veber, D. F., J. Org. Chem., 1985, 50, 4615). The synthesis of 1 from a carbohydrate precursor such as D-mannose (Ghosh, A. K., McKee, S. P., Thompson, W. T., J. Org. Chem., 1991, 56, 6500), or via a .gamma.-ketoester derived from N-Cbz-L-phenylalanine (Hoffman, R. V., Kim, H., Tetrahedron Lett., 1992, 33, 3579), N-benzyl-N-BOC-phenylalanine (Dondoni, A., et al., Tetrahedron Lett., 1992, 33, 7259), or N-phthalimido-phenylalanine (Sakurai, M., et al., Tetrahedron Lett., 1993, 34, 5939), have also been reported.
U.S. Patents which disclose methods for the synthesis of hydroxyethylene dipeptide isosteres include U.S. Pat. No. 5,192,668 entitled "Synthesis of Protease Inhibitor," issued Mar. 9, 1993; U.S. Pat. No. 5,188,950 entitled "Method of Preparing HIV Protease Inhibitors," issued Feb. 23, 1993; U.S. Pat. No. 5,187,074 entitled "Method of Hydroxylation with ATCC 55086," issued Feb. 16, 1993; U.S. Pat. No. 5,175,298 entitled "Dipeptide Hydroxy Ethylene Isostere Synthesis and Intermediate Therefor," issued Dec. 29, 1992; and U.S. Pat. No. 5,169,952 entitled "Stereoselective Production of Hydroxyamide Compounds from Chiral Alpha-Amino Epoxides," issued Dec. 8, 1992.
While these syntheses are successful in producing the target compound, the syntheses proceed with variable stereocontrol, and can exhibit one or more other drawbacks such as a relatively long synthetic sequence, the use of expensive starting materials, or the use of a starting material such as an .alpha.-amino aldehyde which is prone to racemization or which produces variable diastereoselectivity depending on the nature of the "R'" group. For example, the Hoffman process (wherein the hydroxyethylene dipeptide isostere is prepared by the alkylation of a t-butyl .beta.-ketoester with an .alpha.-bromocarboxylic acid), after hydrolysis, decarboxylation and reduction results in a mixture of 4R and 4S isomers in an approximate ratio of 1.8:1, which must be separated. The DeCamp, et al. process uses an .alpha.-amino aldehyde as a starting material that is easily racemized under a variety of experimental conditions. The amino aldehyde is reacted with a titanium homoenolate prepared from ethyl 3-bromopropionate to provide a mixture of (4S/4R) diastereomers that must be separated. The reaction of N,N-dibenzyl-phenylalanine with a dichloroisopropoxytitanium homoenolate using the DeCamp protocol results in a ratio of 4R to 4S diastereomers of greater than 20 to 1.
Another stereoselective synthesis of hydroxyethylene dipeptide isosteres was recently reported by Diederich and Ryckman. Diederich, "Stereoselective Synthesis of a Hydroxyethylene Dipeptide Isostere," Tetrahedron Lett., 1993, 34, 6169-6172. The Diederich synthesis is based on the conversion of a dibenzyl-L-amino acid to the corresponding N'-methyl-O-methylcarboxamide, which is reacted with a Grignard reagent derived from 2-(2-bromoethyl)-1,3-dioxolane or 2-(2-bromoethyl)-1,3-dioxane to produce a (2S)-2-dibenzylamino-5-[1,3]dioxolan-2-yl-1-phenyl-pentan-3-one or (2S)-2-dibenzylamino-5-[1,3]dioxan-2-yl-phenyl-pentan-3-one, respectively. Reduction of the carbonyl moieties provides the desired amino alcohol function with high 4S-stereoselectivity. The C2-substituent is added by conversion of (2S)-2-dibenzylamino-5-[1,3]dioxolan-2-yl-1-phenyl-pentan-3-one or (2S)-2-dibenzylamino-5-[1,3]dioxan-2-yl-phenyl-pentan-3-one to its corresponding lactone, followed by alkylation of the lactone and ring opening. Diederich's synthesis suffers from the disadvantages that not all of the reagents are commercially available (the Grignard reagents have to be generated), the reagents can be relatively expensive, and the oxidation step requires chromium, which presents waste disposal problems.
None of the known syntheses for hydroxyethylene dipeptide isosteres provides the optimal combination of the use of stable and inexpensive starting materials, high stereoselectivity, high yield, and minimal number of process steps. In light of the strong need for large quantities of hydroxyethylene dipeptide isosteres for the research and development of HIV-protease inhibitors and renin inhibitors, it would be of benefit to provide an economical method for their synthesis.
Therefore, it is an object of the present invention to provide a method for the preparation of hydroxyethylene dipeptide isosteres that results in a product with (4S,5S) stereochemistry.
It is another object of the present invention to provide a method for the preparation of hydroxyethylene dipeptide isosteres that places a substituent group in the C2-position with the proper configuration.
It is another object of the present invention to provide a method for the preparation of hydroxyethylene dipeptide isosteres that is simple and efficient.
It is another object of the present invention to provide a method for the preparation of hydroxyethylene dipeptide isosteres that can be carried out on a manufacturing scale.